Xue Liqiu, Zhang Rongjun, Chen Jiaxing, Ge Xiaoxia, Chen Jiajing
Department of Pathology, Jinjiang Hospital of Traditional Chinese Medicine, Jinjiang, Quanzhou, People's Republic of China.
Department of Pathology, Jinjiang Municipal Hospital, Fujian Campus of Shanghai Six People's Hospital, Jinjiang, Quanzhou, People's Republic of China.
Int J Womens Health. 2025 May 24;17:1497-1509. doi: 10.2147/IJWH.S509603. eCollection 2025.
Previous studies have reported a link between UDP-glucose ceramide glucosyltransferase (UGCG), immune regulation, and endometriosis (EM). We hypothesized that UGCG inhibitors might exert therapeutic effects on EM. Therefore, in this study, we performed a two-sample, two-step Mendelian randomization (MR) analysis modeling genetic variation of UGCG inhibitors to investigate the causal relationship between genetically determined inhibition, EM, and mediation of immune cells.
Two-sample MR was conducted using genome-wide association study data on inhibition and EM. Furthermore, we adopted strict instrumental variable selection criteria to ensure the robustness of our results and primarily employed the inverse-variance weighted method, along with the weighted median, MR-Egger, and MR-PRESSO methods for sensitivity analyses. Additionally, a two-step MR analysis was performed to investigate the potential role of immune cells in mediating the relationship between inhibition and EM.
inhibition was associated with a decreased EM risk, with an odds ratio of 0.915, 95% confidence interval of 0.859-0.975, and = 0.006, demonstrating the robustness of our results and potential clinical significance of our study. Among 731 types of immune cells analyzed, 12 were significantly associated with inhibition and EM, 8 of which acted as mediators. Terminally differentiated CD4+ T cells (from the maturation stages of the T-cell panel) accounted for the highest proportion of mediating cells (26.727%), whereas immunoglobulin D (IgD) expression on IgD+ CD38 B cells (from the B-cell panel) accounted for the lowest proportion (7.816%).
Inhibiting UGCG activity may reduce the risk of EM, and immune cells may mediate this effect. Our findings provide novel insights for the development of potential therapeutic strategies for EM treatment.
既往研究报道了UDP-葡萄糖神经酰胺葡萄糖基转移酶（UGCG）、免疫调节与子宫内膜异位症（EM）之间的联系。我们推测UGCG抑制剂可能对EM具有治疗作用。因此，在本研究中，我们进行了两样本、两步孟德尔随机化（MR）分析，对UGCG抑制剂的遗传变异进行建模，以研究基因决定的抑制作用、EM以及免疫细胞介导作用之间的因果关系。
使用关于抑制作用和EM的全基因组关联研究数据进行两样本MR分析。此外，我们采用严格的工具变量选择标准以确保结果的稳健性，主要采用逆方差加权法，同时使用加权中位数法、MR-Egger法和MR-PRESSO法进行敏感性分析。另外，进行两步MR分析以研究免疫细胞在介导抑制作用与EM之间关系中的潜在作用。
抑制作用与EM风险降低相关，比值比为0.915，95%置信区间为0.859 - 0.975，P = 0.006，表明我们结果的稳健性以及本研究潜在的临床意义。在分析的731种免疫细胞类型中，有12种与抑制作用和EM显著相关，其中8种起介导作用。终末分化的CD4 + T细胞（来自T细胞谱系的成熟阶段）在介导细胞中所占比例最高（26.727%），而IgD + CD38 B细胞（来自B细胞谱系）上的免疫球蛋白D（IgD）表达所占比例最低（7.816%）。
抑制UGCG活性可能降低EM风险，且免疫细胞可能介导这一效应。我们的研究结果为开发EM治疗的潜在策略提供了新的见解。
